July 31, 2011 Researchers have developed a toolkit that enables them to turn off targeted cell populations while leaving others unaffected.
Led by Susan Dymecki, a professor of genetics at Harvard Medical School, the group focused on serotonin-producing neurons, observing how mice behave in a normal environment when suddenly their serotonin neurons are turned down. While their findings affirm earlier studies, the researchers used a technique that is non-invasive and does not require anesthesia, surgeries, or knocking out a gene -- each of which can cause problems when interpreting results.
"By selectively and abruptly switching off the serotonin-producing cells, we can get a definite idea of what bodily functions the serotonin cells specifically control," said Dymecki. "These findings and the new tools in neuroscience that it brings to the table will help us understand the role of serotonergic neurons in many human disorders."
One such disorder particularly relevant to these findings is Sudden Infant Death Syndrome, or SIDS.
These findings will appear in the July 29 edition of the journal Science.
The mammalian brain contains multiple chemical messengers, called neurotransmitters, which transfer information between nerve cells in order to regulate basic behaviors and functions like walking, eating, and sleeping. Serotonin is a major brain neurotransmitter produced solely by cells in the lower brain, or brainstem. Cells that make serotonin can convey information to large numbers of neurons distributed throughout the brain and can affect behavior as complex as mood.
In order to better understand how these serotonin-producing cells in the brain relate to basic physiology, Russell Ray and Rachael Brust, a postdoctoral researcher and a graduate student in Dymecki's lab, along with Jun Chul Kim, a prior postdoctoral fellow in Dymecki's lab who is now at the University of Toronto, and Andrea Corcoran, a postdoctoral researcher in the lab of Eugene Nattie at Dartmouth Medical School along with George Richerson, a professor of neurology at the University of Iowa, developed and characterized a method for selectively silencing neurons that produce serotonin.
The group began with a molecule genetically engineered by Bryan Roth and his colleagues at the University of North Carolina School of Medicine. Using a method that Dymecki's group had developed and optimized over the years called "intersectional genetics," they incorporated this molecule, a receptor, into the serotonin-producing brain cells in mice. As a result, the mice naturally generated this "unnatural" receptor on the surface of their serotoninergic neurons.
Receptors are key players in cellular communications, the initial recipients of chemical signals sent by other cells. Here, the researchers injected the mice with clozapine-N-oxide, a chemical compound designed to bind to and trigger the engineered receptor. Within minutes, the chemical and the foreign receptor acted together as a kind of dimmer switch, dampening the action of serotonin networks in the brains of these mice.
"This gave us the ability to selectively shut down serotonergic neuron function in the mouse brain," said Ray. "The mice remained awake, thus we could study their behavior in a normal environment."
When serotonergic neuron activity was diminished, the mice lost their capacity to maintain body temperature, and their temperatures plummeted to that of their surrounding environment.
Also, the ability of the mice to physiologically respond to elevations in carbon dioxide levels -- typically in the form of heavy, rapid breathing to rid the body of excessive carbon dioxide buildup before it might reach dangerous levels -- was roughly half that of normal mice when serotonergic neuron activity was low.
"What is particularly powerful to note is that we were able to study the mice both before and after we switched off the serotonergic neurons," said Ray. "We were able to demonstrate that prior to activating this foreign receptor switch -- that is prior to silencing the serotonin neurons -- the mice responded normally to temperature and carbon dioxide challenges."
The researchers believe this work may help us better understand the mechanisms underlying SIDS in humans.
Recent findings from the lab of Hannah Kinney at Children's Hospital Boston suggest that SIDS babies may have a deficiency of serotonin in circuits in the brainstem. Such deficiencies may lead directly to abnormal responses to elevated levels of carbon dioxide, such as when a baby rebreathes exhaled stale gases with high carbon dioxide levels while lying facedown.
"These infants may be vulnerable to sudden death due to impaired serotonin function in brainstem circuits important for protective responses to life threatening challenges, such as increased levels of carbon dioxide," said Dymecki. "What's more, a SIDS-vulnerable infant may be less equipped to maintain a normal body temperature."
Dymecki, along with her lab members and her colleagues at Dartmouth and University of Iowa, are now investigating how serotonergic neurons influence vital functions in young mice that are in the comparable age range to human infants at peak risk for SIDS. They also plan to use this genetic platform to selectively turn off subsets of serotonergic neurons, to better understand their specific functioning in health, and in other serotonin-linked disorders.
This research was funded by the National Institutes of Health.
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- R. S. Ray, A. E. Corcoran, R. D. Brust, J. C. Kim, G. B. Richerson, E. Nattie, S. M. Dymecki. Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition. Science, 2011; 333 (6042): 637 DOI: 10.1126/science.1205295
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